Current Opinion in Lipidology:
NUTRITION AND METABOLISM: Edited by Paul Nestel and Ronald P. Mensink
Plant sterols and atherosclerosis
Silbernagel, Günthera; Genser, Berndb,c; Nestel, Pauld; März, Winfriedb,e,f
aDivision of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, Eberhard-Karls-University Tübingen, Tübingen
bMannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
cInstituto de Saúde Coletiva, Federal University of Bahia, Salvador, Brazil
dBaker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
eClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
fSynlab Academy, Synlab GmbH, Mannheim, Germany
Correspondence to Dr Guenther Silbernagel, MD, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, Eberhard-Karls-University Tübingen, Otfried-Müller-Strassee 10, 72076 Tübingen, Germany. Tel: +49 7071 29 80687; fax: +49 7071 29 5712; e-mail: firstname.lastname@example.org
Purpose of review: Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe.
Recent findings: Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health.
Summary: Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double–blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.
The American Heart Association has recommended the use of plant-sterol-containing functional foods for the treatment of hypercholesterolemia [1,2]. In agreement, the European Society of Cardiology and the European Atherosclerosis Society have recently pointed out in their guidelines for the management of dyslipidemias that the use of plant sterols is associated with a decrease in LDL cholesterol . Nevertheless, there is still no consensus within the scientific community whether lowering LDL cholesterol with plant sterols is well tolerated [4–6].
Skepticism is based on three important findings: first, the rare autosomal recessive genetic disorder sitosterolemia, which is characterized by up to 50-fold increased circulating plant sterol levels, may predispose to early onset cardiovascular disease . Second, several reports in the general population have found positive associations of circulating plant sterols with cardiovascular risk [8,9]. Third, intake of plant-sterol-containing functional foods is associated with an about two-fold increase in circulating plant sterols . The discussion has further been fueled by the detection of plant sterols in carotid atherosclerotic plaques . Not only that, but also plant sterol intake was found to be related to increased tissue plant sterol content in aortic valve cusps .
On the other hand, the regular administration of plant sterols is associated with a decrease in LDL cholesterol of about 13 mg/dl . Such a reduction would be expected to translate into a considerable decrease of cardiovascular risk . Furthermore, studies in experimental animals have clearly shown that the use of plant sterols is associated with a decrease in LDL cholesterol caused atherosclerosis [15,16].
The current review aims to summarize the recent attempts to investigate the potential impact of plant sterols on atherosclerosis. We have focused on the genetic analyses involving the ATP binding cassette transporter G5/G8 (ABCG5/G8) and ABO loci, on studies addressing the associations of circulating plant sterols with cardiovascular disease, on novel dietary intervention studies and studies using food frequency questionnaires, and last but not least on interesting novel data in experiments animals.
ABCG5 and ABCG8 form a heterodimeric transmembrane transporter which is highly expressed in enterocytes and which protects the human body against the accumulation of plant sterols [17,18]. Severe loss-of-function mutations in the genes encoding ABCG5/G8 are causally related to sitosterolemia [17,18]. In the past, several common variants in ABCG5/G8 were found to be associated with circulating plant sterols . In addition, some data indicated relationships of ABCG5/G8 single-nucleotide polymorphisms (SNPs) with the risk of cardiovascular disease . Overall, however, the SNPs reported in the past (rs6720173, rs11887534, rs4148211, rs4148217, and rs6544718) seemed to be of minor importance .
In contrast, a recent genomewide association (GWA) study in 1495 participants of the KORA cohort found rs4245791 and rs41360247 in the ABCG8 gene and rs657152 in the ABO gene to be strongly associated with circulating campesterol, sitosterol, and brassicasterol. These associations have been confirmed in two independent cohorts with 1157 and 1760 participants . In the next step, the authors demonstrated in a meta-analysis comprising 13 764 people with cardiovascular disease and 13 630 healthy controls that the plant sterol raising alleles in rs4245791, rs41360247, and rs657152 were associated with increased cardiovascular risk . The results of this study have been supported by other large-scale GWA studies. Most importantly, rs4299376, which is in close linkage disequilibrium with rs4245791, and rs579459, which is in close linkage disequilibrium with rs657152, were associated with cardiovascular risk in a study comprising 15 596 people with coronary artery disease and 34 992 controls. These relationships have been replicated in another 17 121 coronary artery disease cases and 40 473 controls. [22▪▪]. Furthermore, several SNPs in the ABO gene including rs514659 and rs657152 were found to predict the risk for myocardial infarction in 9427 people with angiographically verified coronary artery disease [23▪]. Finally, rs579459 in ABO was related to cardiovascular risk in a meta-analysis comprising 143 677 individuals [24▪].
The associations of plant sterol raising alleles in ABCG8 and ABO with cardiovascular disease remain, however, associations and do not necessarily prove a causal role for plant sterols in atherogenesis. Of relevance, circulating plant sterols are surrogate markers for intestinal cholesterol absorption [25▪]. Furthermore, the risk alleles in ABCG8 and ABO have been found not only to correlate with higher circulating plant sterols, but also with elevated total and LDL cholesterol levels [21,22▪▪,24▪,26–29]. Hence, the relationships of the ABCG8 and ABO SNPs with cardiovascular risk rather reflect atherogenic effects of elevated total and LDL cholesterol levels in high cholesterol absorbers . ABO exhibits still further pleiotropy showing associations with concentrations of von Willebrand factor, coagulation factor VIII, intercellular adhesion molecule-1, P-selectin, and E-selectin, which all may affect cardiovascular risk [31–33].
To sum up, genetic studies revealed that ABCG8 and ABO loci modulate plant sterol levels and cardiovascular risk. However, the data certainly do not verify that in the general population moderately elevated circulating plant sterols are atherogenic.
CIRCULATING PLANT STEROLS AND CARDIOVASCULAR DISEASE
We have examined the relationships of circulating plant sterols and their ratios to cholesterol with cardiovascular disease in a meta-analysis comprising 17 studies published between January 1950 and April 2010 with a total 11 182 participants [34▪▪]. Considerable heterogeneity was observed among the studies included [34▪▪]. Of interest, there were reports on positive, absent, and negative associations between plant sterols and cardiovascular disease [34▪▪]. The meta-analysis showed no significant association between campesterol and sitosterol and cardiovascular disease, both for their absolute concentrations and for their ratios to cholesterol (Table 1) [34▪▪]. In contrast to people with sitosterolemia, who display about 50-fold elevated circulating plant sterol concentrations, consumers of plant sterol margarines only have an about two-fold increase in circulating plant sterols [7,10]. This magnitude of variation in circulating plant sterols was covered by the meta-analysis (Table 2) [34▪▪]. Nevertheless, we want to point out that the participants of the studies included in the meta-analysis did not take plant-sterol-enriched foods.
A few studies on circulating plant sterols and cardiovascular disease were published after April 2010 and, therefore, were not included in the meta-analysis. One prospective study in a cohort of 623 people, who were older than 75 years, showed an association of low circulating sitosterol with increased mortality . Similarly, campesterol and the campesterol and sitosterol to cholesterol ratios showed weak negative associations with carotid intima-media thickness measured by ultrasound in 583 people aged 25–60 years without prevalent cardiovascular disease . On the contrary, a study comprising 177 patients without diabetes who were referred for coronary angiography reported increased campesterol-to-cholesterol ratio in the subgroup with coronary artery disease . Significant associations between circulating plant sterols and cardiovascular disease were absent in a cohort of 127 people on and off hemodialysis .
In interpreting the associations between circulating plant sterols and cardiovascular disease, it should again be considered that plant sterols reflect intestinal cholesterol absorption [25▪]. In fact, we think that the repeatedly observed positive correlation between circulating plant sterols and cardiovascular disease is accounted for by the atherogenic effects of high cholesterol absorption . This view is supported by the finding that circulating cholestanol was increased in people with cardiovascular disease and also predictive of future cardiovascular events [30,39–42]. Thus, a raised phytosterol concentration may be a marker of disturbed cholesterol metabolism and not itself causally related to atherosclerosis. However, the positive associations of high cholesterol absorption and consequently high circulating plant sterols with cardiovascular risk may be blunted or even reversed by several factors. For example, cholesterol absorption and thus circulating plant sterols are decreased in disorders characterized by increased cholesterol synthesis such as the metabolic syndrome, type 2 diabetes, and fatty liver [25▪]. Another relevant confounder is the positive correlation of circulating plant sterols with high vegetable and fruit intake .
In short, there is currently no evidence that moderately increased circulating plant sterols seen in the general population are associated with increased cardiovascular risk.
DIETARY INTERVENTION STUDIES AND STUDIES ON FOOD FREQUENCY QUESTIONNAIRES
There is solid evidence that the use of plant-sterol-enriched functional foods will reduce LDL cholesterol . Two recent dietary intervention studies deserve closer attention. Jenkins et al. report on a very accurate randomized trial comparing the effects of a dietary portfolio including plant sterols, soy protein, viscous fibers, and nuts with a low-saturated fat diet in 351 hyperlipidemic people over a period of 6 months. Notably, a substantial decrease in LDL cholesterol of −26 mg/dl was achieved for the dietary portfolio, whereas only a decrease of −8 mg/dl was achieved for the low-fat diet . A considerable portion of the LDL cholesterol reduction was attributed to the plant sterol supplementation . Lin et al. performed a crossover study in 22 individuals who received three different treatments lasting 3 weeks each, namely ezetimibe placebo plus phytosterol placebo, ezetimibe 10 mg/day plus phytosterol placebo, and ezetimibe 10 mg/day plus phytosterol supplement 1.9 g/2000 kcal. They found that ezetimibe plus phytosterol treatment was superior to ezetimibe alone in terms of lowering LDL cholesterol. Although both studies were able to confirm beneficial effects of dietary plant sterols on LDL cholesterol, they raised some skepticism because the ultimate proof that plant sterols will reduce cardiovascular risk is currently not available [46,47]. A prospective, randomized, and controlled dietary intervention study would be needed to conclusively demonstrate a reduction in cardiovascular endpoints by plant sterol supplementation. However, because of feasibility problems such a study is not planned so far.
The potentially vasculoprotective role of plant sterol supplementation has been supported by a randomized placebo-controlled trial comprising 108 patients with the metabolic syndrome. This study revealed that phytosterol supplementation decreases plasma small and dense LDL levels .
It has widely been speculated that persons heterozygous for mutations causing sitosterolemia were particularly vulnerable against plant sterols. A very important clarification of this concern has been achieved by Myrie et al.[49▪▪]. They were able to show that heterozygous mutation carriers are not specifically predisposed to excessive increases in circulating phytosterols following plant sterol supplementation.
Miettinen et al. provided further evidence that plant sterol supplementation is associated with an increase in circulating plant sterols. However, they also made the novel observation that the phytosterol content in carotid atherosclerotic plaques does not seem to be markedly higher in consumers of plant sterol [50▪] margarines than in nonconsumers.
Another approach to study the impact of dietary plant sterols on lipids and atherogenesis is the evaluation of food frequency questionnaires . A previous report in 37 150 male and 40 502 female participants of the Västerbotten Intervention Program, who were aged 29–61 years, demonstrated high dietary intake of plant sterols to be associated with lower circulating LDL cholesterol . The results of the Swedish study were lately confirmed by a Chinese community-based cross-sectional study comprising 1160 men and 2780 women aged 31–75 years. Of interest, the authors also observed a trend toward an inverse relationship between plant sterol intake and ultrasound measurements of the carotid intima-media thickness .
Briefly, dietary plant sterol supplementation is effective in the treatment of hypercholesterolemia. However, an association of high plant sterol intake with a reduction in cardiovascular risk has not been demonstrated. As long as a controlled intervention trial is not available, large, prospective cohort studies with detailed and periodic dietary assessments may help to improve the level of evidence on the relationship between plant sterol supplementation and cardiovascular disease .
STUDIES IN EXPERIMENTAL ANIMALS
A few interesting novel studies in experimental animals may help us to better understand the role of plant sterols in vascular disease. Weingärtner et al. reported that plant sterol supplementation was effective in reducing serum cholesterol and in retarding atherosclerotic lesion formation in apoE-knockout mice on a Western-type diet. However, plant sterol administration at the same time impaired endothelial vasodilation. This finding may have been explained by an increase in a harmful monocyte subpopulation in response to plant sterol administration. Another investigation showed that phytosterol supplementation is associated with a decrease in lipoprotein oxidizability in mice on a high-fat diet . Likewise, plant sterol supplementation had beneficial effects on plasma lipids and, in contrast to the study by Weingärtner et al., also improved vascular function in hamsters . Finally, we want to highlight a relatively new mouse model which may serve as a resource for studying sitosterolemia .
All in all, animal data tend to support vasculoprotective effects of dietary plant sterol supplementation.
Regular intake of plant sterols is associated with a decrease in LDL cholesterol of about 13 mg/dl and an increase in circulating plant sterols of about 0.5 mg/dl [10,13]. Hence, consumption of plant sterols should reduce cardiovascular risk if circulating plant sterols are not about 26 times more atherogenic than LDL cholesterol. Current evidence argues against such a strong relationship between circulating plant sterols and cardiovascular disease. Thus, we share the view of the American Heart Association that the additive use of plant sterols should be considered for lowering LDL cholesterol [1,2]. Nevertheless, speculation about a potentially atherogenic role of plant sterols will probably continue unless proven otherwise.
B.G. and W.M. received grants/lecture fees from Danone Research, Palaiseau, France.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 88).
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ABO; atherosclerosis; ATP binding cassette transporter G5/G8; campesterol; sitosterol
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